EP2900670A1 - Substituierte indazolpyrrolopyrimidine zur behandlung von hyperfoliferativen erkrankungen - Google Patents

Substituierte indazolpyrrolopyrimidine zur behandlung von hyperfoliferativen erkrankungen

Info

Publication number
EP2900670A1
EP2900670A1 EP13766088.2A EP13766088A EP2900670A1 EP 2900670 A1 EP2900670 A1 EP 2900670A1 EP 13766088 A EP13766088 A EP 13766088A EP 2900670 A1 EP2900670 A1 EP 2900670A1
Authority
EP
European Patent Office
Prior art keywords
indazol
pyrrolo
pyrimidin
ylamino
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13766088.2A
Other languages
English (en)
French (fr)
Inventor
Lars Wortmann
Ulrich Klar
Georg Kettschau
Florian PÜHLER
Philip Lienau
Kirstin Petersen
Andrea HÄGEBARTH
Detlev Sülzle
Keith Graham
Anja Richter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Priority to EP13766088.2A priority Critical patent/EP2900670A1/de
Publication of EP2900670A1 publication Critical patent/EP2900670A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to substituted indazol-pyrrolopyrimidine compounds of general formula I as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyperproliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
  • the present invention relates to chemical compounds that inhibit MKNK1 kinase (also known as MAP Kinase interacting Kinase, Mnk1 ) and/or MKNK2 kinase (also known as MAP Kinase interacting Kinase, Mnk2).
  • MKNK1 kinase also known as MAP Kinase interacting Kinase, Mnk1
  • MKNK2 kinase also known as MAP Kinase interacting Kinase, Mnk2
  • Human MKNKs comprise a group of four proteins encoded by two genes (Gene symbols: MKNK1 and MKNK2) by alternative splicing.
  • the b-forms lack a MAP kinase-binding domain situated at the C-terminus.
  • the catalytic domains of the MKNK1 and MKNK2 are very similar and contain a unique DFD (Asp-Phe-Asp) motif in subdomain VII, which usually is DFG (Asp-Phe-Gly) in other protein kinases and suggested to alter ATP binding [Jauch et al. , Structure 13, 1559-1568, 2005 and Jauch et al. , EMBO J25, 4020-4032, 2006] .
  • MKNKI a binds to and is activated by ERK and p38 MAP Kinases, but not by JNK1 .
  • MKNK2a binds to and is activated only by ERK.
  • MKNKI b has low activity under all conditions and MKNK2b has a basal activity independent of ERK or p38 MAP Kinase.
  • MKNKs have been shown to phosphorylate eukaryotic initiation factor 4E (elF4E), heterogeneous nuclear RNA-binding protein A1 (hnRNP A1 ), polypyrimidine-tract binding protein-associated splicing factor (PSF), cytoplasmic phospholipase A2 (cPLA2) and Sprouty 2 (hSPRY2) [Buxade M et al. , Frontiers in Bioscience 5359-5374, May 1 , 2008] .
  • elF4E eukaryotic initiation factor 4E
  • hnRNP A1 heterogeneous nuclear RNA-binding protein A1
  • PSF polypyrimidine-tract binding protein-associated splicing factor
  • cPLA2 cytoplasmic phospholipase A2
  • hSPRY2 Sprouty 2
  • elF4E is an oncogene that is amplified in many cancers and is phosphorylated exclusively by MKNKs proteins as shown by KO-mouse studies [Konicek et al. , Cell Cycle 7: 16, 2466-2471 , 2008; Ueda et al. , Mol Cell Biol 24, 6539-6549, 2004] .
  • elF4E has a pivotal role in enabling the translation of cellular mRNAs.
  • elF4E binds the 7-methylguanosine cap at the 5 ' end of cellular mRNAs and delivers them to the ribosome as part of the elF4F complex, also containing elF4G and elF4A.
  • elF4E a pool of mRNAs is exceptionally dependent on elevated elF4E activity for translation.
  • These so-called "weak mRNAs” are usually less efficiently translated due to their long and complex 5 ' UTR region and they encode proteins that play significant roles in all aspects of malignancy including VEGF, FGF-2, c-Myc, cyclin D1 , survivin, BCL-2, MCL-1 , MMP-9, heparanase, etc.
  • Expression and function of elF4E is elevated in multiple human cancers and directly related to disease progression [Konicek et al. , Cell Cycle 7: 16, 2466-2471 , 2008] .
  • MKNK1 and MKNK2 are the only kinases known to phosphorylate elF4E at Ser209. Overall translation rates are not affected by elF4E phosphorylation, but it has been suggested that elF4E phosphorylation contributes to polysome formation (i.e. multiple ribosome on a single mRNA) that ultimately enables more efficient translation of "weak mRNAs" [Buxade M et al. , Frontiers in Bioscience 5359-5374, May 1 , 2008] .
  • phosphorylation of elF4E by MKNK proteins might facilitate elF4E release from the 5 ' cap so that the 48S complex can move along the "weak mRNA" in order to locate the start codon [Blagden SP and Willis AE, Nat Rev Clin Oncol. 8(5):280-91 , 201 1 ] . Accordingly, increased elF4E phosphorylation predicts poor prognosis in non-small cell lung cancer patients [Yoshizawa et al. , Clin Cancer Res. 16(1 ):240-8, 2010] .
  • MKNK1 constitutively active, but not kinase-dead, MKNK1 also accelerated tumor growth in a model using ⁇ -Myc transgenic hematopoietic stem cells to produce tumors in mice. Comparable results were achieved, when an elF4E carrying a S209D mutation was analyzed. The S209D mutation mimicks a phosphorylation at the MKNK1 phosphorylation site. In contrast a non-phosphorylatable form of elF4E attenuated tumor growth [Wendel HG, et al., Genes Dev. 21 (24):3232-7, 2007].
  • a selective MKNK inhibitor that blocks elF4E phosphorylation induces apoptosis and suppresses proliferation and soft agar growth of cancer cells in vitro.
  • This inhibitor also suppresses outgrowth of experimental B16 melanoma pulmonary metastases and growth of subcutaneous HCT1 16 colon carcinoma xenograft tumors without affecting body weight [Konicek et al., Cancer Res. 71 (5): 1849-57, 201 1 ].
  • Screening of a cohort of pancreatic ductal adenocarcinoma patients by immunohistochemistry showed that elF4E phosphorylation correlated with disease grade, early onset of disease and worse prognosis.
  • MNK/elF4E pathway represents an escape route utilized by pancreatic ductal adenocarcinoma cells to withstand chemotherapeutic treatments (e.g Gemcitabine) [Adesso L, et al. , Oncogene. 2012 Jul 16] .
  • Rapamycin activated MKNK1 kinase activity in multiple myeloma cell lines and primary specimens by a MKNK-dependent mechanism.
  • Pharmacological inhibition of MKNK activity or genetic silencing of MKNK1 prevented a rapalog- induced upregulation of c-myc IRES activity.
  • WO 2008/006547 (Develogen) is related to pyrrolopyrimidine compounds and their use for the treatment of diseases which can be influenced by the inhibition of the kinase activity Mnk1 and/or Mnk2.
  • the general formula (1 ) of claim 1 of the PCT patent application does not cover the indazol-pyrrolopyrimidine compounds of the present invention.
  • one single indazol-pyrrolopyrimidine compound is disclosed.
  • the pyrrolopyrimidine core of this compound is not substituted at the five-membered ring.
  • particular preferred compounds of the invention exhibit IC50 values below 10 ⁇ in in vitro biological screening assays for inhibition of Mnk 1 and/or Mnk 2 kinase activity.
  • a value of 10 ⁇ is rather high compared to the IC50 value of 70 nM reported for CGP052088 on page 9 of the specification of the PCT application.
  • WO 2008/006547 neither teaches nor suggests the substituted indazol- pyrrolopyrimidine compounds of the present invention and their superior inhibitory effect on MKNK1 and/or MKNK2.
  • W01998/23613 A1 relates to fused bicyclic pyrimidine derivates as EGFR inhibitors.
  • the generic formula I of claim 1 of the PCT patent application inter alia covers indazol-pyrrolopyrimidine compounds, however, there is no specific example of an indazol-pyrrolopyrimidine compound disclosed in said patent application.
  • W01996/40142 A1 relates to heterocyclic ring-fused pyrimidine derivates as EGFR inhibitors.
  • the generic formula I of claim 1 of the PCT patent application inter alia covers indazol-pyrrolopyrimidine compounds.
  • indazol-pyrrolopyrimidine compound disclosed (example 10).
  • the pyrrolopyrimidine core of this compound is not substituted at the five-membered ring.
  • WO2003/013541 A1 relates to 7H-pyrrolo[2,3-d]pyrimidine derivates as EGFR inhibitors.
  • the generic formula I of claim 1 of the PCT patent application inter alia covers indazol-pyrrolopyrimidine compounds, however, there is no specific example of an indazol-pyrrolopyrimidine compound disclosed in said patent application.
  • US 2012/0149902 relates to pyrrolo[2,3-d]pyrimidine derivates as HER2 inhibitors.
  • the generic formula I of claim 1 of the US patent application inter alia covers indazol-pyrrolopyrimidine compounds. Two single examples of indazol- pyrrolopyrimidine compounds are disclosed in the specification of said patent application (Example 1 -9, Reference Example 6-5) which are disclaimed hereinafter.
  • WO2007/1 17465 A2 discloses indazole compounds that inhibit one or more receptor, or non-receptor, tyrosine or serine/threonine kinase.
  • the generic formula (I) of claim 1 of the PCT patent application inter alia covers indazol- pyrrolopyrimidine compounds.
  • the PCT patent application discloses two indazol- pyrrolopyrimidine compounds which bear a substituent at the five-membered ring of the pyrrolopyrimidine core (Example #3) which are therefore disclaimed hereinafter.
  • WO 2006/017443 A2 discloses aryl-amino substituted pyrrolopyrimidine compounds as inhibitors of different kinases. MKNK1 and/ MKNK2 are not mentioned.
  • the generic formula I of claim 1 of the PCT patent application inter alia covers indazol- pyrrolopyrimidine compounds. There are some indazol-pyrrolopyrimidine compounds disclosed in the PCT patent applications which bear a substituent at the five-membered ring of the pyrrolopyrimidine core. These compounds are disclaimed from the compounds of the present invention.
  • said compounds of the present invention have surprisingly been found to effectively inhibit MKNK1 kinase and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by MKNK1 kinase, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • R 1a represents a hydrogen atom or a halogen atom or cyano-, Ci -C 3 -alkyl- or
  • R 1 b , R 1 c , R 1d are the same or different and are independently selected from R 1 ;
  • R 1 represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-,
  • R 2a , R 2b are the same or different and are independently selected from R 2 with the proviso that at least one of R 2a and R 2b is different from hydrogen;
  • R 2 represents a hydrogen atom or a halogen atom or a group selected from:
  • R 3a , R 3b are the same or different and are independently selected from R 3 ;
  • R 3 represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-,
  • R 5a , R 5b , R 5c are the same or different and are independently selected from R 5 ;
  • R 5 represents a hydrogen atom, a Ci -C 6 -alkyl- or a C3-C 6 -cycloalkyl- group ; or
  • q represents an integer of 0, 1 , 2 or 3; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; wherein the following compounds are excluded:
  • Phenyl 4-[4-(1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro- 2H-pyridine-1 -carboxylate, tert-Butyl 4-[4-(1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6- dihydro-2H-pyridine-1 -carboxyamide,
  • the present invention further relates to methods of preparing compounds of general formula I, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
  • halogen atom is to be understood as meaning a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.
  • Ci -C6-alkyl is to be understood as preferably meaning a linear or branched, saturated, hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g.
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci -C 4 -alkyl”), e.g. a methyl, ethyl, propyl, butyl, /so-propyl, /so-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms ("Ci -C3-alkyl”), e.g.
  • C2-C 6 -alkylene is to be understood as preferably meaning a linear or branched, saturated, bivalent hydrocarbon group having 2, 3, 4, 5 or 6 carbon atoms, e.g. an ethylene, n-propylene, n-butylene, n-pentylene, 2-methylbutylene, n-hexylene, 3-methylpentylene group, or an isomer thereof.
  • said group is linear and has 2, 3, 4 or 5 carbon atoms (“C2-Cs-alkylene”), e.g.
  • C3-C 4 -alkylene an ethylene, n-propylene, n-butylene, n-pentylene group, more particularly 3 or 4 carbon atoms
  • C3-C 4 -alkylene e.g. an n-propylene or n-butylene group.
  • a Co-alkylene- group represents a direct bond
  • Ci-alkylene stands for a methylene group.
  • the term "halo-Ci -C 6 -alkyl” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci -C 6 -alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F.
  • Said halo-Ci -C 6 -alkyl group is, for example, -CF 3 , -CHF2, -CH2F, -CF2CF 3 , or -CH 2 CF 3 .
  • Ci -C6-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -0-(Ci -C 6 -alkyl), in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
  • halo-Ci -C6-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci -C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F.
  • Said halo-Ci -C 6 -alkoxy group is, for example, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCF 2 CF 3 , or -OCH 2 CF 3 .
  • Ci -C6-alkoxy-Ci -C6-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci -C 6 -alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci -C 6 -alkoxy group, as defined supra, e.g.
  • halo-Ci -C6-alkoxy-Ci -C6-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci -C6-alkoxy-Ci -C 6 -alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom.
  • said halogen atom is F.
  • Said halo-Ci -C6-alkoxy-Ci -C 6 -alkyl group is, for example, -CH 2 CH 2 OCF 3 , -CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 2 F, -CH 2 CH 2 OCF 2 CF 3 , or -CH 2 CH 2 OCH 2 CF 3 .
  • C 2 -C 6 -alkenyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C 2 -C 3 -alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
  • Said alkenyl group is, for example, a vinyl, allyl, (f)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (f)-but-2-enyl, (Z)-but-2-enyl, (f)-but-1 -enyl, (Z)-but-l -enyl, pent-4-enyl, (f)-pent-3-enyl, (Z)-pent-3-enyl, (E) -pent-2-enyl, (Z)-pent-2-enyl, (f)-pent- l -enyl, (Z)-pent-1 -enyl, hex-5-enyl
  • C2-C 6 -alkynyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl").
  • Said C2-C 6 -alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl, but- 1 -ynyl, but-2-ynyl, but-3-ynyl, pent- 1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl,
  • alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-inyl.
  • C3-Cio-cycloalkyl is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C3-Ci o-cycloalkyl").
  • Said C3-Ci o-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring.
  • said ring contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl").
  • C 4 -Cio-cycloalkenyl is to be understood as preferably meaning a monovalent, mono-, or bicyclic hydrocarbon ring which contains 4, 5, 6, 7, 8, 9 or 10 carbon atoms and one, two, three or four double bonds, in conjugation or not, as the size of said cycloalkenyl ring allows.
  • Said C 4 -Ci o-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, or cyclohexenyl or a bicyclic hydrocarbon, e.g. :
  • said 3- to 10-membered heterocycloalkyl can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
  • said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example.
  • Said heterocycloalkyl can be bicyclic, such as, without being limited thereto, a
  • 5.5- membered ring e.g. a hexahydrocyclopenta[c]pyrrol-2(1 H)-yl ring, or a
  • heterocycloalkenyl are e.g.
  • heterocyclyl represents both, 3- to 10-membered heterocycloalkyl and 4- to 10-membered heterocycloalkenyl.
  • aryl is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 1 3 or 14 carbon atoms (a "C 6 -Ci 4 -aryl” group), particularly a ring having 6 carbon atoms (a "C 6 -aryl” group), e.g. a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms (a "C9-aryl” group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl” group), e.g.
  • the aryl group is a phenyl group.
  • heteroaryl is understood as preferably meaning a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 1 3 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc. , and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
  • benzo derivatives thereof such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc. ; or azocinyl, indolizinyl, purinyl, etc.
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
  • Ci -C 6 as used throughout this text, e.g. in the context of the definition of "d -Ce-alkyl", “Ci -Ce-haloalkyl", “Ci -Ce-alkoxy”, or “Ci -Ce-haloalkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “Ci -C 6 " is to be interpreted as any sub-range comprised therein, e.g.
  • C2-C6 as used throughout this text, e.g. in the context of the definitions of "C2-C 6 -alkenyl” and “C2-C6-alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C2-C6” is to be interpreted as any sub- range comprised therein, e.g. Ci-Cb , C 3 -Cs , C 3 -C 4 , C2-C 3 , C2-Q , C2-C5 ; particularly C2-C 3 .
  • C 3 -C 6 as used throughout this text, e.g. in the context of the definition of "C 3 -C 6 -cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C 3 -C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 6 , C 4 -Cs , C 3 -Cs , C 3 -C 4 , C 4 -C 6 , C5-C6 ; particularly C 3 -C 6 .
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom ' s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • leaving group refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halo, in particular chloro, bromo or iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo- benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl-benzene)sulfonyloxy,
  • protecting group is a protective group attached to a nitrogen in intermediates used for the preparation of compounds of the general formula I. Such groups are introduced e.g. by chemical modification of the respective amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for amino groups are descibed for example in T.W. Greene and P.G.M.
  • said groups can be selected from substituted sulfonyl groups, such as mesyl-, tosyl- or phenylsulfonyl-, acyl groups such as benzoyl, acetyl or tetrahydropyranoyl-, or carbamate based groups, such as tert. -butoxycarbonyl (Boc), or can include silicon, as in e.g. 2- (trimethylsilyl)ethoxymethyl (SEM) .
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 l, 124 l, 129 l and 131 l, respectively.
  • Certain isotopic variations of a compound of the invention for example, those in which one or more radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution studies.
  • Tritiated and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • the compounds of the present invention may contain sulphur atoms which are asymmetric, such as an asymmetric sulphoxide or sulphoximine group, of structure:
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • Pure stereoisomers can be obtained by resolution of racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g.
  • chiral HPLC columns with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Daicel, e.g. , Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of the present invention may exist as tautomers.
  • any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1 H tautomer, a 2H tautomer, or a AH tautomer, or even a mixture in any amount of said 1 H, 2H and AH tautomers, namely :
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N -oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • polar solvents in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 -19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4-butantriol, or with a quarternary ammonium salt, such as tetramethylammonium, tetraethylammonium, tetra(n- propyl)ammonium, tetra
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, Ci-C 6 alkoxymethyl esters, e.g. methoxymethyl, Ci-C 6 alkanoyloxymethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • [alpha] -acyloxyalkyl ethers include acetoxymethoxy and
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl nd N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
  • the present invention covers compounds of general formula I :
  • C 3 -C7-cycloalkyloxy- (3- to 10-membered heterocycloalkyl)-0-, -NR 5a R 5b , -SCF 3 or -SF5 group; represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C 3 -C 6 -cycloalkyl,
  • (CH2)q-X- (CH2)p-R 3 said groups being optionally substituted, identically or differently, with 1 , 2, 3, 4 or 5 R 4 groups ; represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C 3 -C 6 -cycloalkyl-,
  • R 3 represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-,
  • R 3a represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-,
  • R 3b represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-,
  • R 3a or R 3b represent a 3- to 10-membered heterocycloalkyl- or a 4- to 10-membered heterocycloalkenyl- group, which is optionally substituted, one or more times, identically or differently, with Ci-C 6 -alkyl-, halo-, hydroxyl- or cyano-;
  • R 5 represents a hydrogen atom, a Ci-C 6 -alkyl- or C3-C 6 -cycloalkyl- group ;
  • R 5a represents a hydrogen atom, a Ci-C 6 -alkyl- or C3-C 6 -cycloalkyl- group ;
  • R 5b represents a hydrogen atom, a Ci-C 6 -alkyl- or C3-C 6 -cycloalkyl- group ;
  • R 5c represents a hydrogen atom, a Ci-C 6 -alkyl- or C3-C 6 -cycloalkyl- group ; or
  • p represents an integer of 0, 1 , 2 or 3;
  • q represents an integer of 0, 1 , 2 or 3; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; for the inhibition of MKNK1 and/or MKNK2.
  • the present invention covers the compounds of general formula I as defined supra for the treatment of a disease, wherein the treatment comprises the inhibition of MKNK1 and/or MKNK2 in a diseased organism.
  • the disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response.
  • the disease is a disease in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the MKNK1 pathway.
  • the disease is a disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haematological tumour, a solid tumour and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • leukaemias and myelodysplastic syndrome e.g. leukaemias and myelodysplastic syndrome
  • malignant lymphomas e.g. leukaemias and myelodysplastic syndrome
  • head and neck tumours including brain tumours and brain metastases
  • the present invention covers the compounds of general formula I as defined supra per se, wherein the following compouns are excluded: wherein the following compounds are excluded: (4-((1 H-indazol-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(naphthalen-1 - yl)methanone,
  • Phenyl 4-[4-(1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro- 2H-pyridine-1 -carboxylate, tert-Butyl 4-[4-(1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6- dihydro-2H-pyridine-1 -carboxyamide,
  • R 1a represents a hydrogen atom or a halogen atom or a methyl- group.
  • R 1 a represents a hydrogen atom.
  • the invention relates to compounds of formula I, supra, wherein R 1 b represents a hydrogen atom or a halogen atom or a cyano-, Ci-C 3 -alkyl-, halo-Ci-C 3 -alkyl-, -NR 5a R 5b , Ci-C 3 -alkoxy- or halo-Ci-C 3 -alkoxy- group.
  • R 1 b represents a hydrogen atom or a halogen atom or a cyano- or Ci-C3-alkyl- group.
  • R 1 b represents a hydrogen atom or a halogen atom.
  • R 1 b represents a hydrogen atom.
  • R 1 c represents a hydrogen atom or a halogen atom or a cyano-, Ci-C 3 -alkyl-, halo-Ci -C 3 -alkyl-, Ci-C 3 -alkoxy- or
  • R 1c represents a hydrogen atom or a halogen atom or a cyano- or Ci-C 3 -alkyl- group.
  • R 1c represents a hydrogen atom or a halogen atom.
  • R 1 c represents a hydrogen atom.
  • R 1 d represents a hydrogen atom or a halogen atom or a cyano-, Ci-C 3 -alkyl-, halo-Ci -C 3 -alkyl-, Ci-C 3 -alkoxy- or
  • R 1d represents a hydrogen atom or a halogen atom or a cyano- or Ci-C 3 -alkyl- group.
  • R 1d represents a hydrogen atom or a halogen atom.
  • R 1 d represents a hydrogen atom.
  • each of R 1a , R 1 b , R 1 c , and R 1d represents a hydrogen atom.
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C3-C 6 -cycloalkyl-, aryl-, heteroaryl-, cyano-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, (CH2)q-X-(CH2) P -R 3 ;
  • Ci-C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C3-C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, aryl- or heteroaryl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C3-C 6 -cycloalkyl-, cyano-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, (CH2)q-X-(CH2) P -R 3 ;
  • 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C3-alkyl-, -C2-C3-alkenyl-R 3 , C3-C 6 -cycloalkyl-, cyano-, 4- to 6-membered heterocycloalkyl-,
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C3-alkyl-, -C2-C3-alkenyl-R 3 , halo-Ci -C3-alkyl-, (CH2)q-X- (CH2)p-R 3 ; wherein said Ci -C3-alkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci -C3-alkyl-, -C2-C3-alkenyl-R 3 , (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 3 -alkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2a represents a 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group, wherein said
  • 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2a represents a 4- to 6-membered heterocycloalkyl- or 4- to 6-membered heterocycloalkenyl- group, wherein said
  • 4- to 6-membered heterocycloalkyl- or 4- to 6-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 3 -alkyl-, -C 2 -C 3 -alkenyl-R 3 , (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 3 -alkyl- group is optionally substituted, identically or differently, with 1 or 2 R 4 groups.
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 3 -alkyl-, -C2-C 3 -alkenyl-R 3 , (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 3 -alkyl- group is optionally substituted with one R 4 group.
  • R 2a represents a hydrogen atom.
  • R 2a represents a group selected from: Ci-C 3 -alkyl-, -C2-C 3 -alkenyl-R 3 , (CH2)q-X- (CH2) P -R 3 ; wherein said Ci-C 3 -alkyl- group is optionally substituted with one R 4 group; wherein q is 0 or 1 ; wherein p is 0 or 1 ; and wherein X is a bond or a group selected from:
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 6 -alkyl-, -C 2 -C6-alkenyl-R 3 , -C 2 -C6-alkinyl-R 3 , C 3 -C 6 -cycloalkyl-, (CH2)q-X-(CH 2 )p-R 3 , halo-Ci -C 3 -alkyl-,
  • Ci -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 2a is not any of the following groups:
  • z represents heteroaryl, -(Ci-C6-alkylene)-0-(Ci-C 6 -alkyl),
  • z represents a group selected from:
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci -C 6 -alkyl-, C3-C 6 -cycloalkyl-, (CH2)q-X-(CH2) P -R 3 , halo-Ci -C 3 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 ,
  • Ci -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci -C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C 3 -C 6 -cycloalkyl-, -(CH 2 )q-X-(CH2) P -R 3 , halo-Ci -C 3 -alkyl-,
  • Ci -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 2a does not comprise a moiety
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci -C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , Cs-Ce-cycloalkyl-, -(CH 2 )q-X-(CH 2 )p-R 3 , halo-Ci -C 3 -alkyl-,
  • Ci -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci -C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C 3 -C 6 -cycloalkyl-, -(CH 2 ) q -X-(CH 2 ) P -R 3 , halo-Ci -C 3 -alkyl-,
  • Ci -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 2a does not comprise a moiety
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci -C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C 3 -C 6 -cycloalkyl-, aryl-, heteroaryl-, halo-Ci -C 3 -alkyl-, cyano-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 6 -alkyl-, C3-C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, aryl- or heteroaryl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , -C2-C 6 -alkinyl-R 3 , C3-C 6 -cycloalkyl-, halo-Ci -C 3 -alkyl-, cyano-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 3 -alkyl-, -C2-C 3 -alkenyl-R 3 , C 3 -C 6 -cycloalkyl-, halo-Ci-C 3 -alkyl-, cyano-, 4- to 6-membered heterocycloalkyl-, 4- to 6-membered heterocycloalkenyl-,
  • Ci-C 3 -alkyl-, C 3 -C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl- or 4- to 6-membered heterocycloalkenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 3 -alkyl-, 4- to 6-membered heterocycloalkenyl- group, aryl, heteroaryl, (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 3 -alkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 3 -alkyl-, 4- to 6-membered heterocycloalkenyl- group, aryl, heteroaryl; wherein said Ci-C 3 -alkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 3 -alkyl-, (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 3 -alkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 3 -alkyl-, (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 3 -alkyl- group is optionally substituted, identically or differently, with 1 or 2 R 4 groups.
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 3 -alkyl-, (CH2)q-X-(CH2) P -R 3 ; wherein said Ci-C 3 -alkyl- group is optionally substituted with one R 4 group.
  • R 2b represents a hydrogen atom or a halogen atom or a Ci -C 3 -alkyl- group; wherein said Ci -C 3 -alkyl- group is optionally substituted with one R 4 group.
  • R 2b represents a hydrogen atom or a halogen atom or a Ci-C 3 -alkyl- group.
  • R 2b represents a hydrogen atom. In another preferred embodiment R 2b represents a halogen atom.
  • R 2b represents a Ci-C 3 -alkyl- group.
  • R 2b represents a group selected from: C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-, (CH2)q-X-(CH2) P -R 3 ; said groups being optionally substituted, identically or differently, with 1 , 2, 3, 4 or 5 R 4 groups.
  • R 2b represents a group selected from: 4- to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-, (CH2)q-X-(CH2) P -R 3 ; said groups being optionally substituted, identically or differently, with 1 , 2, 3, 4 or 5 R 4 groups.
  • R 2b represents a group selected from: 4- to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-; said groups being optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 2b represents a (CH2)q-X-(CH2) P -R 3 group.
  • R 2a and R 2b represents a group selected from: (CH2)q-X-(CH2) P -R 3 , C3-C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-; wherein said C3-C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl- is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups; and the other one of R 2a and R 2b represents a hydrogen atom or a halogen atom or a group selected from: Ci -C 6 -alkyl-, halo-Ci-C 3 -alkyl-, cyano-. In another preferred embodiment one of R 2a and R 2b represents a group selected from:
  • R 2a and R 2b represents a group selected from:
  • R 2a and R 2b are different from hydrogen. That means: when R 2a is a hydrogen atom, then R 2b is not a hydrogen atom and vice versa.
  • X represents -(NR 3a )-.
  • R 3 is not an aryl- group.
  • R 3 represents a hydrogen atom or a group selected from Ci-C 6 -alkyl-, C3-C6-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, halo-Ci -C3-alkyl- ; wherein said Ci-C 6 -alkyl-, C3-C6-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl- or heteroaryl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3 represents a hydrogen atom or a group selected from Ci-C 6 -alkyl-, C3-C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, halo-Ci-C3-alkyl- ; wherein said Ci-C 6 -alkyl-, C3-C 6 -cycloalkyl- or 3- to 10-membered heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3 represents a hydrogen atom or a group selected from Ci -C3-alkyl-, C3-C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl-, halo-Ci-C3-alkyl- ; wherein said Ci -C3-alkyl-, C3-C 6 -cycloalkyl- or 4- to 6-membered heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3 represents a hydrogen atom or a group selected from Ci-C3-alkyl-, 4- to 6-membered heterocycloalkyl-; wherein said Ci-C3-alkyl- or 4- to 6-membered heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3 represents a hydrogen atom or a group selected from Ci-C3-alkyl-, 4- to 6-membered heterocycloalkyl-; wherein said Ci-C3-alkyl- or 4- to 6-membered with one R 4 group.
  • R 3 represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-, aryl-; said groups being optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3a represents a hydrogen atom or a group selected from Ci -C3-alkyl-, C3-C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl-, aryl-, heteroaryl-, halo-Ci -C3-alkyl- ; wherein said Ci-C3-alkyl-, C3-C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl-, aryl- or heteroaryl- group is optionally substituted, identically or differently, with 1 , 2, 3, 4 or 5 R 4 groups.
  • R 3a represents a hydrogen atom or a group selected from Ci -C 3 -alkyl-, C 3 -C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl-, halo-Ci -C 3 -alkyl- ; wherein said Ci -C 3 -alkyl-, C 3 -C 6 -cycloalkyl- or 4- to 6-membered heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3a represents a hydrogen atom or a Ci -C 6 -alkyl- group ; wherein said Ci -C 6 -alkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3a represents a hydrogen atom or a Ci -C 6 -alkyl- group ; wherein said Ci -C 6 -alkyl- group is optionally substituted, identically or differently, with 1 or 2 R 4 groups.
  • R 3a represents a hydrogen atom or a Ci -C 3 -alkyl- group ; wherein said Ci -C 3 -alkyl- group is optionally substituted, identically or differently, with 1 or 2 R 4 groups.
  • R 3a represents a hydrogen atom
  • Ci -C 3 -alkyl- group wherein said Ci -C 3 -alkyl- group is optionally substituted one R 4 group.
  • R 3a represents a hydrogen atom or a Ci -C 3 -alkyl- group.
  • R 3a represents a hydrogen atom.
  • R 3b represents a hydrogen atom or a group selected from Ci -C 3 -alkyl-, C 3 -C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl-, aryl-, heteroaryl-, halo-Ci -C 3 -alkyl- ; wherein said Ci -C 3 -alkyl-, C 3 -C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl-, aryl- or heteroaryl- group is optionally substituted, identically or differently, with 1 , 2, 3, 4 or 5 R 4 groups.
  • R 3b represents a hydrogen atom or a group selected from Ci -C 3 -alkyl-, C 3 -C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl-, halo-Ci-C 3 -alkyl- ; wherein said Ci -C 3 -alkyl-, C 3 -C 6 -cycloalkyl- or 4- to 6-membered heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3b represents a hydrogen atom or a Ci-C 6 -alkyl- group ; wherein said Ci-C 6 -alkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups.
  • R 3b represents a hydrogen atom or a Ci-C 6 -alkyl- group ; wherein said Ci-C 6 -alkyl- group is optionally substituted, identically or differently, with 1 or 2 R 4 groups.
  • R 3b represents a hydrogen atom or a Ci-C 3 -alkyl- group ; wherein said Ci-C 3 -alkyl- group is optionally substituted, identically or differently, with 1 or 2 R 4 groups.
  • R 3b represents a hydrogen atom
  • Ci-C 3 -alkyl- group wherein said Ci -C 3 -alkyl- group is optionally substituted one R 4 group.
  • R 3b represents a hydrogen atom or a Ci-C 3 -alkyl- group.
  • R 3b represents a hydrogen atom.
  • R 3 together with R 3a or R 3b represent a 3- to 10-membered heterocycloalkyl- or a 4- to 10-membered heterocycloalkenyl- group, which is optionally substituted, one or more times, identically or differently, with Ci-C 3 -alkyl-, halo-, hydroxyl-, cyano-.
  • R 3 together with R 3a represent a 3- to 10-membered heterocycloalkyl- or a 4- to 10-membered heterocycloalkenyl- group, which is optionally substituted, one or more times, identically or differently, with Ci-C 3 -alkyl-, halo-, hydroxyl-, cyano-.
  • R 3 together with R 3a or R 3b represent a 3- to 10-membered heterocycloalkyl- group, which is optionally substituted, one or more times, identically or differently, with Ci-C 3 -alkyl-, halo-, hydroxyl-, cyano-.
  • R 3 together with R 3a or R 3b represent a 4- to 8-membered heterocycloalkyl- group, which is optionally substituted, one or more times, identically or differently, with Ci-C 3 -alkyl-, halo-, hydroxyl-, cyano-.
  • R 3 together with R 3a or R 3b represent a 5- to 7-membered heterocycloalkyl- group, which is optionally substituted, one or more times, identically or differently, with Ci-C 3 -alkyl-, halo-, hydroxyl-, cyano-.
  • R 3 together with R 3a or R 3b represent a 5- to 6-membered heterocycloalkyl- group, which is optionally substituted, one or more times, identically or differently, with Ci-C 3 -alkyl-, halo-, hydroxyl-, cyano-.
  • R 3 together with R 3a or R 3b represent a 3- to 10-membered heterocycloalkyl- group, which is optionally substituted, one or more times, identically or differently, with halo-.
  • R 3 together with R 3a represent a 3- to 10-membered heterocycloalkyl- group, which is optionally substituted, one or more times, identically or differently, with halo-.
  • R 4 represents halo-, hydroxy-, cyano-, nitro-, Ci-C 6 -alkyl-, C2-C 6 -alkenyl-, C2-C 6 -alkynyl-, halo-Ci -C 6 -alkyl-, Ci-C 6 -alkoxy-, halo-Ci-C 6 -alkoxy-, hydroxy-Ci -C 6 -alkyl-, Ci-C6-alkoxy-Ci-C 6 -alkyl-, halo-Ci-C6-alkoxy-Ci -C 6 -alkyl-.
  • R 4 represents halo-, hydroxy-, cyano-, nitro-, Ci-C 3 -alkyl-, C 2 -C 3 -alkenyl-, C 2 -C 3 -alkynyl-, halo-Ci -C 3 -alkyl-, Ci-C 3 -alkoxy-, halo-Ci-C 3 -alkoxy-, hydroxy-Ci -C 3 -alkyl-, Ci-C 3 -alkoxy-Ci-C 3 -alkyl-, halo-Ci-C 3 -alkoxy-Ci -C 3 -alkyl-.
  • R 4 represents halo-, hydroxy-, Ci -C 3 -alkyl-, C 2 -C 3 -alkenyl-, C 2 -C 3 -alkynyl-, halo-Ci -C 3 -alkyl-, Ci-C 3 -alkoxy-, halo-Ci -C 3 -alkoxy-, hydroxy-Ci-C 3 -alkyl-, Ci -C 3 -alkoxy-Ci-C 3 -alkyl-, halo-Ci-C 3 -alkoxy-Ci -C 3 -alkyl-.
  • R 4 represents halo-, Ci -C 3 -alkyl-, C 2 -C 3 -alkenyl-, C 2 -C 3 -alkynyl-, halo-Ci-C 3 -alkyl-, Ci-C 3 -alkoxy-, halo-Ci-C 3 -alkoxy-, Ci -C 3 -alkoxy-Ci -C 3 -alkyl-, halo-Ci -C 3 -alkoxy-Ci -C 3 -alkyl- .
  • R 4 represents halo-, Ci-C 3 -alkyl-, halo-Ci-C 3 -alkyl-, Ci-C 3 -alkoxy-, halo-Ci -C 3 -alkoxy-.
  • R 4 represents halo-, hydroxy- or -NR 5a R 5b .
  • R 5 represents a hydrogen atom or a Ci -C 6 -alkyl- group.
  • R 5 represents a hydrogen atom or a Ci -C 3 -alkyl- group.
  • R 5a represents a hydrogen atom or a Ci -C 6 -alkyl- group.
  • R 5a represents a hydrogen atom or a Ci -C 3 -alkyl- group.
  • R 5b represents a hydrogen atom or a Ci -C 6 -alkyl- group.
  • R 5b represents a hydrogen atom or a Ci -C 3 -alkyl- group.
  • R 5c represents a hydrogen atom or a Ci -C 6 -alkyl- group.
  • R 5c represents a hydrogen atom
  • Ci -C 3 -alkyl- group Ci -C 3 -alkyl- group.
  • R 5a and R 5b or R 5a and R 5c , or
  • R 5a and R 5b together form a C 3 -C 4 alkylene group.
  • R 5a and R 5c together form a C 3 -C 4 alkylene group.
  • R 5b and R 5c together form a C 3 -C 4 alkylene group.
  • p represents an integer of 0, 1 or 2. In another preferred embodiment p represents an integer of 0.
  • p represents an integer of 1 . In another preferred embodiment p represents an integer of 2. In another preferred embodiment q represents an integer of 0, 1 or 2. In another preferred embodiment q represents an integer of 0. In another preferred embodiment q represents an integer of 1 .
  • q represents an integer of 2.
  • p represents an integer of 0 and q represents an integer of 1 .
  • p represents an integer of 1 and q represents an integer of 0. In another preferred embodiment p represents an integer of 0 and q represents an integer of 0.
  • p represents an integer of 1 and q represents an integer of 1 .
  • the invention relates to compounds of formula I, according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the invention relates to compounds of formula I:
  • R 1d represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-,
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from:
  • R 2a is not any of the following groups:
  • z represents heteroaryl, -(Ci-C6-alkylene)-0-(Ci-C 6 -alkyl),
  • z represents a group selected from:
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from:
  • R 3 represents a hydrogen atom or a group selected from: Ci -C 3 -alkyl-,
  • heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 3a represents a hydrogen atom or a group selected from: Ci -C 3 -alkyl-,
  • Ci -C 3 -alkyl-, C 3 -C 6 -cycloalkyl- or 4- to 6-membered heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 3b represents a hydrogen atom or a group selected from: Ci -C 3 -alkyl-,
  • heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups; or
  • R 5 represents a hydrogen atom, a Ci -C 3 -alkyl- or C 3 -C 6 -cycloalkyl- group ;
  • R 5a represents a hydrogen atom, a Ci -C 3 -alkyl- or C 3 -C 6 -cycloalkyl- group ;
  • R 5b represents a hydrogen atom, a Ci -C 3 -alkyl- or C 3 -C 6 -cycloalkyl- group ;
  • R 5c represents a hydrogen atom, a Ci -C 3 -alkyl- or C 3 -C 6 -cycloalkyl- group ;
  • q represents an integer of 0, 1 or 2 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • R 1a represents a hydrogen atom
  • R 1 b represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-,
  • R 1c represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-,
  • R 1d represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-,
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from:
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from:
  • heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • Ci -C 3 -alkyl-, C 3 -C 6 -cycloalkyl- or 4- to 6-membered heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups; or
  • R 5 represents a hydrogen atom or a Ci -C 3 -alkyl- group ;
  • R 5a represents a hydrogen atom or a Ci -C 3 -alkyl- group ;
  • R 5b represents a hydrogen atom or a Ci -C 3 -alkyl- group ;
  • R 5c represents a hydrogen atom or a Ci -C 3 -alkyl- group ;
  • q represents an integer of 0, 1 or 2 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the invention relates to compounds of formula I:
  • R 1a represents a hydrogen atom
  • R 1 b represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-,
  • R 1c represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-,
  • R 1d represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-,
  • 10-membered heterocycloalkenyl- is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 2a and R 2b represents a hydrogen atom or a halogen atom or a group selected from: Ci-C 6 -alkyl-, halo-Ci -C 3 -alkyl-, cyano-; with the proviso that R 2a does not comprise a moiety selected from:
  • R 3 represents a hydrogen atom or a group selected from: Ci -C 3 -alkyl-,
  • heterocycloalkyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 3a represents a hydrogen atom or a group selected from: Ci -C 3 -alkyl-,
  • Ci -C 3 -alkyl- group is optionally substituted, identically or differently, with 1 or 2 R 4 groups;
  • R 3b represents a hydrogen atom or a group selected from: Ci -C 3 -alkyl-,
  • Ci -C 3 -alkyl- group is optionally substituted, identically or differently, with 1 or 2 R 4 groups; or
  • R 5 represents a hydrogen atom or a Ci -C3-alkyl - group ;
  • R 5a represents a hydrogen atom or a Ci -C3-alkyl - group ;
  • R 5b represents a hydrogen atom or a Ci -C3-alkyl - group ;
  • R 5c represents a hydrogen atom or a Ci -C3-alkyl - group ;
  • q represents an integer of 0, 1 or 2 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • R 1a represents a hydrogen atom
  • R 1 b represents a hydrogen atom
  • R 1c represents a hydrogen atom
  • R 1d represents a hydrogen atom
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from:
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from:
  • R 3 represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-,
  • R 3a represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-,
  • R 3b represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-,
  • R 3 together with R 3a or R 3b represent a 3- to 10-membered heterocycloalkyl- or a 4- to 10-membered heterocycloalkenyl- group, which is optionally substituted, one or more times, identically or differently, with Ci -C 3 -alkyl-, halo-, hydroxyl- or cyano-;
  • R 5 represents a hydrogen atom, a Ci -C 6 -alkyl- or C 3 -C 6 -cycloalkyl- group ;
  • R 5a represents a hydrogen atom, a Ci -C 6 -alkyl- or C 3 -C 6 -cycloalkyl- group ;
  • R 5b represents a hydrogen atom, a Ci -C 6 -alkyl- or C 3 -C 6 -cycloalkyl- group ;
  • R 5c represents a hydrogen atom, a Ci -C 6 -alkyl- or C 3 -C 6 -cycloalkyl- group ;
  • the invention relates to compounds of formula I:
  • R 1a represents a hydrogen atom
  • R 1b represents a hydrogen atom
  • R 1c represents a hydrogen atom
  • R 1d represents a hydrogen atom
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from:
  • R 2b represents a hydrogen atom or a halogen atom or a group selected from:
  • R 3 represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-, aryl-; said groups being optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 3a represents a hydrogen atom or a Ci -C 6 -alkyl- group
  • R 3b represents a hydrogen atom or a Ci -C 6 -alkyl- group
  • R 3 together with R 3a or R 3b represent a 3- to 10-membered heterocycloalkyl- or a 4- to 10-membered heterocycloalkenyl- group, which is optionally substituted, one or more times, identically or differently, with Ci -C 3 -alkyl-, halo-, hydroxyl- or cyano-;
  • R 4 represents halo-, hydroxy-, cyano-, nitro-, Ci -C 6 -alkyl-, C2-C 6 -alkenyl-,
  • R 5 represents a hydrogen atom or a Ci -C 6 -alkyl- group ;
  • R 5a represents a hydrogen atom or a Ci -C 6 -alkyl- group ;
  • R 5b represents a hydrogen atom or a Ci -C 6 -alkyl- group ;
  • R 5c represents a hydrogen atom or a Ci -C 6 -alkyl- group ; represents an integer of 0 or 1 ;
  • the invention relates to compounds of formula I:
  • R 1a represents a hydrogen atom
  • R 1 b represents a hydrogen atom
  • R 1c represents a hydrogen atom
  • R 1d represents a hydrogen atom; represents a hydrogen atom or a halogen atom or a group selected from: Ci -C 6 -alkyl-, -C2-C 6 -alkenyl-R 3 , 3- to 10-membered heterocycloalkyl-,
  • R 2a represents a hydrogen atom or a halogen atom or a group selected from:
  • X represents a bond or a bivalent group selected from:
  • R 3 represents a hydrogen atom or a group selected from: Ci -C 6 -alkyl-, aryl-; said groups being optionally substituted, identically or differently, with 1 , 2 or 3 R 4 groups;
  • R 3a represents a hydrogen atom or a Ci-C 6 -alkyl- group
  • R 3b represents a hydrogen atom or a Ci-C 6 -alkyl- group
  • R 3 together with R 3a or R 3b represent a 3- to 10-membered heterocycloalkyl- group, which is optionally substituted, one or more times, identically or differently, with Ci-C 3 -alkyl-, halo-, hydroxyl- or cyano-;
  • R 4 represents halo-, hydroxy- or -NR 5a R 5b ;
  • R 5 represents a hydrogen atom or a Ci-C 6 -alkyl- group ;
  • R 5a represents a hydrogen atom or a Ci-C 6 -alkyl- group ;
  • R 5b represents a hydrogen atom or a Ci-C 6 -alkyl- group ;
  • R 5c represents a hydrogen atom or a Ci-C 6 -alkyl- group ; p represents an integer of 0 or 1 ;
  • q represents an integer of 0 or 1 ;
  • the present invention relates to any sub-combination within any embodiment or aspect of the present invention of compounds of general formula I, supra. More particularly still, the present invention covers compounds of general formula I which are disclosed in the Examples section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • the present invention relates to a method of preparing compounds of general formula I, supra, in which method an intermediate compound of general formula II :
  • R 1 a , R 1 b , R 1 c , and R 1 d are as defined for the compounds of general formula I, supra, is allowed to react with an intermediate compound of general formula III :
  • LG represents a leaving group, such as a halogen atom or a trifluoromethylsulphonyloxy or nonafluorobutylsulphonyloxy group for example
  • PG represents a hydrogen atom or a protective group such as mesyl-, tosyl-, phenylsulfonyl-, tetrahydropyranoyl-, tert.-butyloxycarbonyl- or acyl- group thus providing a compound of general formula I :
  • R 1 a , R 1 b , R 1c , R 1d , R 2a and R 2b are as defined for the compounds of general formula I, supra.
  • the present invention relates to intermediate compounds for the preparation of the compounds of general formula I, supra.
  • the present invention relates to intermediate compounds of general formula III :
  • R 2a and R 2b are as defined for the compounds of general formula I, supra, LG represents a leaving group, and PG represents a hydrogen atom or a protective group.
  • Scheme 1 exemplifies one route that allows variations and modifications in R 2a or R 2b at different stages of the synthesis.
  • other routes may be used to synthesise the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis.
  • the order of transformations exemplified in the Scheme is therefore not intended to be limiting.
  • interconversion of any of the substituents, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , LG or PG can be achieved before and/or after the exemplified transformations.
  • Compounds of formula IV can be synthesized by reacting compound VI with carbonyl compound V in an inert solvent like, for example, ethanol or methanol at temperatures ranging from room temperature to the boiling point of the solvent, for example.
  • an inert solvent like, for example, ethanol or methanol
  • Compounds of formula III can also be synthesized by heating compounds of formula IV with or without an inert additive or solvent like, for example, xylol, 2-[2-(2-tert- butoxyethoxy)ethoxy]-2-methylpropane or 1 -methoxy-2-(2-methoxyethoxy)ethane at temperatures ranging from 100° C to 400° C and pressures ranging from 1 atmosphere to 50 bar. Heating can be optionally performed using microwave irradiation optionally with an additive to improve the absorption of microwave radiation like, for example, an ionic liquid like, for example, 3- (triphenylphosphonio)-propane-l -sulfonate.
  • an inert additive or solvent for example, xylol, 2-[2-(2-tert- butoxyethoxy)ethoxy]-2-methylpropane or 1 -methoxy-2-(2-methoxyethoxy)ethane
  • Compounds of formula I can be synthesized by reacting compounds of formula II with a compound of general formula VII with R 1a , R 1 b , R 1 c as defined for general formula I.
  • the optionally substituted 5-amino-indazole VII replaces LG in compounds of general formula II to form amines of general formula I.
  • Compounds of general formula I can also be built by Ullmann-type coupling reactions in the presence of suitable catalysts, such as, for example, copper based catalysts like copper(ll)diacetate or copper(l)chloride in the presence of a suitable base, like for example, caesium carbonate starting from compounds of general formula II.
  • suitable catalysts such as, for example, copper based catalysts like copper(ll)diacetate or copper(l)chloride
  • a suitable base like for example, caesium carbonate starting from compounds of general formula II.
  • suitable ligands like ⁇ , ⁇ -dimethylglycine or phenyl hydrogen pyrrolidin-2-ylphosphonate can be added.
  • the reaction can be performed at temperatures ranging from -40°C to the boiling point of the solvent, for example.
  • Said coupling reactions are performed in the presence of suitable catalysts, such as, for example, copper- or palladium based catalysts like, for example, copper(ll)diacetate, copper(l)chloride, Palladium (II) acetate, tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II) chloride or (1 , 1 ,-bis(diphenylphosphino) ferrocene)-dichloropalladium (II) and optionally suitable additives such as, for example, phosphines like, for example, P(oTol) 3 or triphenylphosphine and, and optionally with a suitable base, such as, for example, potassium carbonate, sodium 2-methylpropan-2-olate, tetrabutylammonium fluoride or tribasic potassium phosphate in a suitable solvent, such as, for example, tetrahydrofuran
  • R 1 b , R 1c , R 1d , R 2a or R 2b represent a halogen atom such as, for example, a chlorine, bromine or iodine atom
  • R 1b , R 1c , R 1d , R 2a and/or R 2b can be substituted by nucleophiles like primary or secondary amines, alkoxides, thiolates or carbon anion bearing groups to add secondary or tertiary amines, ethers, thioethers or carbon attached groups.
  • the reactions are performed in inert solvents like tetrahydrofuran.
  • residues in compounds of formulas I, II, III, IV, V, or VII can be optionally modified using, for example, oxidation-, reduction-, substitution- or elimination- reactions and conditions that are well known to a person skilled in the art of organic synthesis.
  • thioethers can be oxidized using oxidation reagents like 3-chlorobenzenecarboperoxoic acid, oxone or dimethyldioxirane in inert solvents like dichloromethane or acetone, respectively.
  • oxidation reagents like 3-chlorobenzenecarboperoxoic acid, oxone or dimethyldioxirane in inert solvents like dichloromethane or acetone, respectively.
  • sulfoxides or sulfones or mixtures thereof will be obtained.
  • the compounds of formula I of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of formula I of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallisation. In some cases, impurities may be removed by stirring using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash chromatography, using for example pre-packed silica gel cartridges, e.g.
  • Separtis such as Isolute ® Flash silica gel or Isolute ® Flash NH2 silica gel in combination with a suitable chromatographic system such as an Isolera system (Biotage) and eluents such as, for example, gradients of hexane/ethyl acetate or dichloromethane/methanol.
  • a suitable chromatographic system such as an Isolera system (Biotage) and eluents such as, for example, gradients of hexane/ethyl acetate or dichloromethane/methanol.
  • the compounds may be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluents such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluents such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a mixture comprising 60.0 mg (307 ⁇ ) 4-chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3- d]pyrimidine (prepared according to intermediate example 1 a), 40.8 mg 1 H- indazol-5-amine (CAS-No: 19335-1 1 -6), 1 .75 mL ethanol and 16.9 ⁇ _ hydrochloric acid (4M in dioxane) was reacted at 1 10° C for 10 hours. The residue was digested in a mixture of diethyl ether and ethanol and dried to give 84.7 mg (90%) of the title compound.
  • a mixture comprising 150 mg (456 ⁇ ) 6-bromo-N-(1H-indazol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (prepared according to example 3), 1.5 ml_ dimethyl sulfoxide, 186 mg sodium methanesulfinate, 25.5 mg ( -benzene-1,2,3,4- tetrayl-1kappa 2 C 1 ,C 2 :2kappa 2 C 3 ,C 4 )[bis(trifluoromethanesulfonatato- kappaO)]dicopper (90%) and ⁇ , ⁇ '-dimethylethylenediamine was heated at 130°C overnight. Dimethyl sulfoxide was added and the product isolated by
  • a mixture comprising 50 mg (152 ⁇ ) 6-bromo-N-(1H-indazol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (prepared according to example 3), 1.8 mL N, N- dimethylformamide, 76.6 mg 4,4,5, 5-tetramethyl-2-(prop-1-en-2-yl)-1, 3,2- dioxaborolane, 105 mg potassium carbonate and 37.2 mg 1,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex was heated at 100° C under microwave irradiation for 2 hours. The product was isolated by chromatography to give 9.0 mg (19%) of the title compound.
  • a mixture comprising 100 mg (304 ⁇ ) 6-bromo-N-(1H-indazol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (prepared according to example 2), 5 mL 1,4- dioxane, 35.1 mg tetrakis(tn ' phenylphosphine)palladium(0), 760 ⁇ _ potassium carbonate (2M in water) was heated at 150°C under microwave irradiation for 1.5 hours. The solvents were removed and the residue purified by chromatography to give 26.3 mg (24%) of the title compound.
  • a mixture comprising 160 mg (551 ⁇ ) N-(1 H-indazol-5-yl)-6-(prop-1 -en-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (prepared according to example 8), 5 ml_ methanol, 2 mL ⁇ , ⁇ -dimethylformamide and 20 mg palladium on charcoal (10%) was heavily stirred under an atmosphere of hydrogen overnight. The catalyst was filtered off and the solvents were removed. The crude product was purified by chromatography to give 4.5 mg mg (2%) of the title compound.
  • a mixture comprising 100 mg (340 ⁇ ) 4-(1 H-indazol-5-ylamino)-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid (prepared according to intermediate example 20a), 3.9 mL N,N-dimethylformamide, 92.8 ⁇ _ 2-aminoethanol, 303 ⁇ _ 2,4,6-tripropyl- 1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide solution (50% in ethyl acetate) and 178 ⁇ _ N-ethyl-N-isopropylpropan-2-amine was stirred at 120°C for 1.25 hours. Water was added, the solution was neutralized by addition of sodium hydroxide solution, the solvents were removed and the residue purified by chromatography to give 10.0 mg (8%) of the title compound.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP13766088.2A 2012-09-26 2013-09-24 Substituierte indazolpyrrolopyrimidine zur behandlung von hyperfoliferativen erkrankungen Withdrawn EP2900670A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP13766088.2A EP2900670A1 (de) 2012-09-26 2013-09-24 Substituierte indazolpyrrolopyrimidine zur behandlung von hyperfoliferativen erkrankungen

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP12186034 2012-09-26
EP13155246 2013-02-14
PCT/EP2013/069779 WO2014048894A1 (en) 2012-09-26 2013-09-24 Substituted indazol-pyrrolopyrimidines useful in the treatment of hyperfoliferative disorders
EP13766088.2A EP2900670A1 (de) 2012-09-26 2013-09-24 Substituierte indazolpyrrolopyrimidine zur behandlung von hyperfoliferativen erkrankungen

Publications (1)

Publication Number Publication Date
EP2900670A1 true EP2900670A1 (de) 2015-08-05

Family

ID=49230781

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13766088.2A Withdrawn EP2900670A1 (de) 2012-09-26 2013-09-24 Substituierte indazolpyrrolopyrimidine zur behandlung von hyperfoliferativen erkrankungen

Country Status (7)

Country Link
US (1) US20150218173A1 (de)
EP (1) EP2900670A1 (de)
JP (1) JP2015531361A (de)
CN (1) CN104781260A (de)
CA (1) CA2885787A1 (de)
HK (1) HK1212340A1 (de)
WO (1) WO2014048894A1 (de)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2592404T3 (es) 2012-05-21 2016-11-30 Bayer Pharma Aktiengesellschaft Benzotienopirimidinas sustituidas
CN104507950B (zh) 2012-05-21 2017-03-22 拜耳医药股份有限公司 噻吩并嘧啶
TW201412740A (zh) 2012-09-20 2014-04-01 Bayer Pharma AG 經取代之吡咯并嘧啶胺基苯并噻唑酮
US9675612B2 (en) 2013-03-06 2017-06-13 Bayer Pharma Aktiengesellschaft Substituted thiazolopyrimidines
KR20180004740A (ko) 2015-04-20 2018-01-12 이펙터 테라퓨틱스, 인크. 암 및 감염 치료에 사용하기 위한 면역 체크포인트 조절 인자의 억제제
US9630968B1 (en) 2015-12-23 2017-04-25 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
EP3397774A1 (de) 2015-12-31 2018-11-07 Effector Therapeutics Inc. Mnk-biomarker und verwendungen davon
CA3034010A1 (en) 2016-08-24 2018-03-01 Arqule, Inc. Amino-pyrrolopyrimidinone compounds and methods of use thereof

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5011472A (en) 1988-09-06 1991-04-30 Brown University Research Foundation Implantable delivery system for biological factors
MX9709867A (es) 1995-06-07 1998-03-31 Pfizer Derivados de pirimidina condensados con un anillo heterociclico, composiciones que contienen los mismos, y uso de los mismos.
WO1998023613A1 (en) 1996-11-27 1998-06-04 Pfizer Inc. Fused bicyclic pyrimidine derivatives
GB0119249D0 (en) 2001-08-07 2001-10-03 Novartis Ag Organic compounds
US7253166B2 (en) * 2003-04-22 2007-08-07 Irm Llc 6-phenyl-7H-pyrrolo[2,3-d]pyrimidine compounds that induce neuronal differentiation in embryonic stem cells
EP1797054A2 (de) 2004-08-02 2007-06-20 OSI Pharmaceuticals, Inc. Arylaminosubstituierte pyrrolopyrimidine als multikinaseinhibierende verbindungen
CN101052629A (zh) * 2004-08-02 2007-10-10 Osi制药公司 芳基－氨基取代的吡咯并嘧啶多激酶抑制化合物
EP2001480A4 (de) 2006-03-31 2011-06-15 Abbott Lab Indazol-verbindungen
EP1889847A1 (de) * 2006-07-10 2008-02-20 DeveloGen Aktiengesellschaft Pyrrolopyrimidine zur pharmazeutischen Anwendung
TW201107328A (en) * 2009-07-28 2011-03-01 Daiichi Sankyo Co Ltd Pyrrolo [2,3-d] pyrimidine derivatives
CA2781287C (en) * 2009-11-18 2018-07-31 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
WO2011082273A2 (en) 2009-12-30 2011-07-07 Arqule, Inc. Substituted pyrrolo-aminopyrimidine compounds

Also Published As

Publication number Publication date
WO2014048894A1 (en) 2014-04-03
HK1212340A1 (en) 2016-06-10
CA2885787A1 (en) 2014-04-03
CN104781260A (zh) 2015-07-15
US20150218173A1 (en) 2015-08-06
JP2015531361A (ja) 2015-11-02

Similar Documents

Publication Publication Date Title
US9382255B2 (en) Substituted pyrrolopyrimidinylamino-benzothiazolones as MKNK kinase inhibitors
EP2852596B1 (de) Thienopyrimidine
US9777004B2 (en) Amino-substituted imidazopyridazines
EP2951175B1 (de) Substituierte pyrazolopyrimidinylamino-indazole
EP2852595B1 (de) Substituierte benzothienpyrimidine
EP2900671A1 (de) Substituierte indazolpyrrolopyrimidine zur behandlung von hyperfoliferativen erkrankungen
CA2837630A1 (en) Substituted aminoimidazopyridazines
WO2013149909A1 (en) Amino-substituted imidazopyridazines
EP2900670A1 (de) Substituierte indazolpyrrolopyrimidine zur behandlung von hyperfoliferativen erkrankungen
EP2852593A1 (de) Substituierte pyrrolopyrimidine
US20160159816A1 (en) Substituted thienopyrimidines and pharmaceutical use thereof
AU2014289415A1 (en) Substituted pyrazolo-pyridinamines
EP3149003A1 (de) Benzothiadiazolamine
EP3149004A1 (de) Substituierte tetrahydropyridothienopyrimidine
TW201348240A (zh) 噻吩并嘧啶

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20150428

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20160913

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20170124